The compound of formula (I) is a an industrially useful compound having the chemical name (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine and the following structure.

WO 03004498 and U.S. Pat. No. 6,699,871 both assigned to Merck & Co., describes a class of beta-amino tetrahydrotriazolo[4,3-a]pyrazines, which are inhibitors of DPP-IV. Disclosed therein are compounds, whose general formula is,

Specifically disclosed in WO 03004498 is (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]-triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine. A specific method for producing Sitagliptin or a salt thereof is disclosed here, depicted by following scheme,

However here the overall chemical and optical yield reported is low and there is no mention of stereoisomeric yield.
Another process for preparation of compound of formula (I) is disclosed in WO 2004087650 which involves the formation of chiral benzyloxyazetidinone intermediate, which later on suitable coupling gives the final product. In this process, chiral reagents have been used from the beginning.
WO 2004085661 describes another process for preparation of chiral beta amino acid derivatives including compound of formula (I). Here S-phenylglycine amide (S-PGA) as a chiral auxiliary is used to get pure Z-enamines from diketone. Here a metal catalyst like PtO2 is used, which is expensive and high pressure is required. Here >90% e.e is reported for the reduced amine.

WO 2004085378 and WO 2006081151 describe a process of preparation of chiral beta amino acid derivatives which includes compound of formula (I). The product is prepared by an enantioselective reduction via transition metal catalyzed asymmetric hydrogenation at high pressure of a prochiral enamine. In WO 2004085378, hydrogenation of enamine is carried out to get final product using a very special catalyst e.g. R,S t-butyl Josiphos, as given below, and another special catalyst is used in WO 2006081151 as given below,

The chiral purity of the product after reduction is claimed to be >70% e.e. The scheme is depicted below:

WO 2005097733 describes a process of preparation of compound of formula (I) by asymmetric hydrogenation using Rhodium metal precursor complexes with chiral mono or bis phosphine ligand. Such mono and bis phosphine ligand disclosed are depicted below:

But in all the above processes, the chiral metal catalysts and the diastereoselective catalysts used are very difficult to prepare and are very expensive. The conditions in which the reactions are carried out are extreme i.e. at high pressure, high temperature, etc. Hence there is a need in the art to develop a simple and efficient process for the bulk production of compound of formula (I).
WO2009070314 discloses process for the preparation of crystalline form I of compound of formula (I), comprising combining a salt of compound of formula (I), water and inorganic base to obtain crystalline form I.
Resolution of an amine to get chiral enantiomer is well known. Even in U.S. Pat. No. 6,699,871, col. 5 and 6 describes the possibility of resolution to get the R-isomer of formula I. The real challenge for a process chemist in resolution is to identify the right resolving agent, solvents, reaction conditions, additives and molar ratio of reagents which can give maximum chirally pure enantiomer in least number of unit operations.
WO2009084024 discloses process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts by resolving the amine with a resolving agent. However the identity of resolving agent is not clear. Most of the time the patent application describe the resolving agent as dibenzyl-L-tartarte salts of formula (I), where as Example 5a and 5c described the use of (−)-dibenzolyl-L-tartaric acid. Surprisingly, claim no-3 discloses the resolving agent (−)-dibenzoyl-L-tartaric acid. Subsequently, claim no. 17 claim dibenzyl-L-tartaric acid diastereomer of formula (I).
Naturally for a person skilled in the art, it is not clear which is the actual resolving agent. Additionally, the same document also describes a resolution of a racemic (50:50 mixture of R & S) amine with a chirally pure resolving agent which gives dibenzolyl-L-tartaric acid diastereomer of formula (I) having ratio of (R) and (S) isomers 50:50 (racemic mixture). Of course, by subsequent solvent treatments the desired diastereomer is obtained by repeated recrystallization to get a chiral purity 85-90%. (Example-5a, 5b and 5c)
People skilled in the art of polymorphism know it very well that the XRD pattern of the compound change by variation in the degree of purity or impurity of the compound. However the document disclosed the XRD and DSC of diastereomer of formula I, having 10-15% of chiral impurity. (Example-5a, 5b and 5c).
The same document also discloses the DSC of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine, which shows only one peak indicating the presence of a single isomer of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine.
WO2009085990 discloses process for the preparation of compound of formula (I) and its pharmaceutically acceptable salts, wherein after the resolution step, chiral purity of di-p-tolyl-L-tartaric acid salt of 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine is not mentioned. In our hand however, chiral purity of the same compound by using same reagent is only 52.46%.
Process as disclosed in WO2009085990 involves the use of sodium cynoborohydride with methanolic HCl (Example 4) during reduction step which may lead to generation of HCN gas. Naturally, generation of such toxic gases can be difficult to manage at large scale level.
Therefor there is a need for a more definitive, efficient, safe and well-characterized, resolution process with step wise tracking of chiral and chemical purity.
The present invention discloses a process of preparation of compound of formula (I) using simple reagents at normal conditions, giving rise to optimum optical yield and purity in minimum number of steps. We herein also disclose certain new impurities of compound of formula (I), process of preparation of these impurities, which may be used as reference standards.
In order to obtain marketing approval for a new drug product, manufacturers must submit to the regulatory authority evidence that the product is acceptable for administration to humans. Such a submission must include impurity profile of the product to demonstrate that the impurities are either absent, or present in a negligible amount. Different regulatory authorities have promulgated guidelines requiring applicants to identify the impurities present in the product and also disclose their concentration in the product. They also provide the maximum level of impurities allowable in the product. Thus, e.g. USFDA recommends that drug applicants identify all the impurities having concentration of 0.1% or greater than in the active ingredient. Therefore, there is a need to check impurity profile and identify the impurities and also their concentration in the active ingredient.
The product mixture of a reaction rarely is a single compound pure enough to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, be present. At certain stages during processing of the Sitagliptin contained in the product mixture into an active pharmaceutical ingredient, it must be analyzed for purity, typically by HPLC or GC analysis.
Generally, impurities (Side products, byproducts and adjunct reagents) are identified spectroscopically and by other physical methods and then the impurities are associated with a peak position in a chromatogram. Thereafter, the impurity can be identified by its position in the chromatogram, which is conventionally measured in minutes between injection of the sample on the column and elution of the particular component through the detector, known as “retention time”. This time period varies daily based upon the condition of the instrumentation and many other factors. To mitigate the effect that such variations have upon accurate identification of an impurity, practitioners use “relative retention time” (RRT) to identified impurities. The RRT of an impurity is its retention time divided by the retention time of some reference marker. Thus, it is sometimes desirable to select an alternative compound that is added to, or is present in, the mixture in an amount significant enough to be detectable and sufficiently low as not to saturate the column and to use that as the reference marker.
Researchers and developers in drug manufacturing understand that a compound in a relatively pure state can be used as a reference standard” (a “reference marker is similar to a reference standard but it is used for qualitative analysis) to quantify the amount of the compound in an unknown mixture. When the compound is used as an “external standard” a solution of a known concentration of the compound is analyzed by the same technique as the unknown mixture.
The reference standard compound also can be used to quantify the amount of another compound in mixture if the “response factor”, which compensates for differences in the sensitivity of the detector to the two compounds, has been predetermined.
The reference standard compound can even be used as an internal standard when the unknown mixture contains some of the reference standard compound by using a technique called “standard addition” wherein at least two samples are prepared by adding known and differing amounts of the internal standard. The proportion of detector response due to the reference standard compound that is originally in the mixture can be determined by extrapolation of a plot of detector response versus the amount of the reference standard compound that was added to each of the sample to zero.